Methods and devices for neuromodulation of the adrenal gland

ABSTRACT

Aspects of the present disclosure are directed toward apparatuses, systems, and methods for delivering therapy to an adrenal gland of a patient. The apparatuses, systems, and methods may include a housing and a plurality of electrodes arranged with the housing. In addition, one or more of the plurality of electrodes may deliver stimulation energy to modulate L-dopa release.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. application Ser. No.15/683,750, filed Aug. 22, 2017, which claims priority to ProvisionalApplication No. 62/378,419, filed Aug. 23, 2016, all of which are hereinincorporated by reference in their entirety.

TECHNICAL FIELD

The present disclosure relates to medical devices and methods forproviding stimulation therapy. More specifically, the disclosure relatesto devices and methods for delivering therapy to an adrenal gland of apatient.

BACKGROUND

Electrical stimulation may be therapeutic in a variety of diseases anddisorders. Leads used in electrical stimulation may be implanted within,adjacent to, or near a targeted area. In certain instances, the lead orleads may be arranged near nerves, muscles, or other tissue.

Dysfunction of the adrenomedullary system, or abnormal levels ofcatecholamines, such as norepinephrine, epinephrine and dopamine, havebeen associated with symptoms including depression, fibromyalgia,chronic fatigue, chronic pain, migraines, orthostatic intolerance,Postural Orthostatic Tachycardia Syndrome (POTS), and other diseasestates. In addition, abnormal levels of L-dopa have been associated withdegenerative diseases such as Parkinson's disease. Stimulation of theadrenal gland can release or block the release of catecholamines and/ormodulate release of L-dopa directly into the bloodstream.

Preganglionic sympathetic axons of the splanchnic nerve terminate atchromaffin cells in the medulla of the adrenal glands. Two populationsof chromaffin cells, one releasing epinephrine and one norepinephrine,demonstrate different innervation patterns. As a result, differentstimulation patterns may be used to alter these levels independently todrive the abnormal levels of catecholamines toward normal levels therebyproviding therapy and/or treatment for one or more of the variousdisease states associated therewith.

SUMMARY

In Example 1, an apparatus for delivering therapy to an adrenal gland ofa patient, the apparatus including: a housing configured to attach to aportion of the adrenal gland of the patient; and a plurality ofstimulation elements arranged with the housing, the plurality ofelectrodes being configured to deliver stimulation energy through atleast one of the plurality of electrodes to modulate release of L-dopainto a bloodstream of the patient.

In Example 2, the apparatus of Example 1, wherein the plurality ofstimulation elements are configured to stimulate the adrenal gland andrelease of L-dopa into the blood stream to maintain dopamine levels ofthe patient within a zone.

In Example 3, the apparatus of Example 1, wherein the housing is aleadless body housing configured to engage the portion of the adrenalgland.

In Example 4, the apparatus of Example 1, wherein the housing is a leadbody configured to engage the portion of the adrenal gland.

In Example 5, the apparatus of Example 1, wherein the plurality ofstimulation elements are configured to deliver at least one ofelectrical stimulation, light stimulation, sound stimulation, thermalstimulation, and magnetic stimulation to the adrenal gland to modulatethe release of L-dopa.

In Example 6, the apparatus of Example 1, further including a sensorconfigured to measure the L-dopa levels within the patient and alter thestimulation energy delivered through the at least one of the pluralityof stimulation elements to maintain the L-dopa release within a zone.

In Example 7, the apparatus of Example 6, wherein the sensor is at leastone of a vascular sensor configured to measure hypotension, a sensorconfigured to measure blood pressure of the patient, a bioimpedencesensor configured to measure blood pressure of the patient, an electoralsensor configured to assess vascular tone or heart pulse transit time,an optical sensor configured to assess vascular tone or heart pulsetransit time, and an accelerometer configured to measure physicalmovement of the patient.

In Example 8, the apparatus of Example 7, wherein the housing includes acommunications component configured to communicate wireless signals, andthe sensor is configured to measure the dopamine levels associated withL-dopa within the patient and communicate feedback to the communicationscomponent via wireless signals to alter the stimulation energy deliveredthrough the at least one of the plurality of stimulation elements tomaintain the L-dopa release within a zone.

In Example 9, the apparatus of Example 1, wherein the plurality ofstimulation elements are configured to delivery stimulation energy on aduty cycle based on a metabolization time of L-dopa within the patient.

In Example 10, the apparatus of Example 1, wherein the delivery ofstimulation energy modulates release of L-dopa to lessen at least one oftremors, muscle rigidity, and bradykinesia of the patient.

In Example 11, the apparatus of Example 1, wherein the plurality ofstimulation elements are configured to intermittently or continuouslyinstruct delivery of the stimulation energy through the plurality ofelectrodes.

In Example 12 a system for delivering therapy to an adrenal gland of apatient, the system including: a housing configured to attach to aportion of the adrenal gland of the patient; a plurality of stimulationelements arranged with the housing, the plurality of electrodes beingconfigured to deliver stimulation energy through at least one of theplurality of electrodes to modulate release of L-dopa into a bloodstreamof the patient; and a sensor configured to measure dopamine levelswithin the patient associated with the L-dopa release and alter thestimulation energy delivered through the at least one of the pluralityof stimulation elements in response thereto.

In Example 13, the system of Example 12, wherein the sensor is at leastone of a vascular sensor configured to measure hypotension, a sensorconfigured to measure blood pressure of the patient, a bioimpedencesensor configured to measure blood pressure of the patient, an electoralsensor configured to assess vascular tone or heart pulse transit time,an optical sensor configured to assess vascular tone or heart pulsetransit time, and an accelerometer configured to measure physicalmovement of the patient.

In Example 14, the system of Example 12, wherein the sensor isconfigured to measure a physical symptom of the patient associated withParkinson's disease.

In Example 15, the system of Example 12, wherein the controller isfurther configured to instruct delivery of the stimulation energythrough the at least one of the plurality of electrodes at a frequencybetween 2 Hz and 20 kHz.

In Example 16, the system of Example 12, wherein the plurality ofstimulation elements are configured to stimulate the adrenal gland andrelease of L-dopa into the blood stream to maintain dopamine levels ofthe patient within a zone

In Example 17, a method of delivering therapy to an adrenal gland of apatient, the method including: delivering a housing to a portion of theadrenal gland of the patient, the housing including a plurality ofstimulation elements arranged with the housing; and deliveringstimulation energy through at least one of a plurality of electrodesleadless implantable medical to modulate aldosterone levels within thepatient.

In Example 18, the method of Example 17, further including deliveringstimulation energy to peripheral sympathetic nerves to modulate therelease of L-dopa into the bloodstream.

In Example 19, the method of Example 17, further including deliveringdeep brain stimulation energy to the patient delivering stimulationenergy.

In Example 20, the method of Example 17, further including measuring aphysical symptom of the patient associated with Parkinson's disease andaltering delivery of the stimulation in response thereto.

While multiple embodiments are disclosed, still other embodiments of thepresent disclosure will become apparent to those skilled in the art fromthe following detailed description, which shows and describesillustrative embodiments of the disclosure. Accordingly, the drawingsand detailed description are to be regarded as illustrative in natureand not restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an example illustration of an adrenal gland therapy system inaccordance with embodiments of the disclosure.

FIG. 2 is a plan view of an adrenal gland therapy system in accordancewith embodiments of the disclosure.

FIG. 3A is an example illustration of an adrenal gland therapy leadconfiguration in accordance with embodiments of the disclosure.

FIG. 3B is an example illustration of another adrenal gland therapy leadconfiguration in accordance with embodiments of the disclosure.

FIG. 3C is an example illustration of another adrenal gland therapy leadconfiguration in accordance with embodiments of the disclosure.

FIG. 4A is an example illustration of an adrenal gland therapy lead anddeployment system in accordance with embodiments of the disclosure.

FIG. 4B is an example illustration of the adrenal gland therapy leadshown in FIG. 4B, deployed from the deployment system in accordance withembodiments of the disclosure.

FIG. 4C is an example illustration of the adrenal gland therapy leadshown in FIGS. 4A-B, deployed on an adrenal gland in accordance withembodiments of the disclosure.

FIG. 4D is an example illustration of the adrenal gland therapy leadshown in FIGS. 4A-C, including tethers in accordance with embodiments ofthe disclosure.

FIG. 5 is an example illustration of adrenal gland therapy leads inaccordance with embodiments of the disclosure.

FIG. 6 is an example illustration of an adrenal gland therapy system inaccordance with embodiments of the disclosure.

FIG. 7A is an example illustration of another adrenal gland therapysystem in accordance with embodiments of the disclosure.

FIG. 7B is an example illustration of a thermoelectric element includedwith the adrenal gland therapy system shown in FIG. 7A in accordancewith embodiments of the disclosure.

FIG. 8 is a schematic block diagram of a leadless implantable medicaldevice, in accordance with aspects of embodiments of the disclosure.

FIG. 9 is a schematic illustration of an implantable system including animplantable medical device (IMD) attached to a portion of a patient'sadrenal gland in accordance with embodiments of the present disclosure.

While the disclosure is amenable to various modifications andalternative forms, specific embodiments have been shown by way ofexample in the drawings and are described in detail below. Theintention, however, is not to limit the disclosure to the particularembodiments described. On the contrary, the disclosure is intended tocover all modifications, equivalents, and alternatives falling withinthe scope of the disclosure as defined by the appended claims.

As the terms are used herein with respect to measurements (e.g.,dimensions, characteristics, attributes, components, etc.), and rangesthereof, of tangible things (e.g., products, inventory, etc.) and/orintangible things (e.g., data, electronic representations of currency,accounts, information, portions of things (e.g., percentages,fractions), calculations, data models, dynamic system models,algorithms, parameters, etc.), “about” and “approximately” may be used,interchangeably, to refer to a measurement that includes the statedmeasurement and that also includes any measurements that are reasonablyclose to the stated measurement, but that may differ by a reasonablysmall amount such as will be understood, and readily ascertained, byindividuals having ordinary skill in the relevant arts to beattributable to measurement error; differences in measurement and/ormanufacturing equipment calibration; human error in reading and/orsetting measurements; adjustments made to optimize performance and/orstructural parameters in view of other measurements (e.g., measurementsassociated with other things); particular implementation scenarios;imprecise adjustment and/or manipulation of things, settings, and/ormeasurements by a person, a computing device, and/or a machine; systemtolerances; control loops; machine-learning; foreseeable variations(e.g., statistically insignificant variations, chaotic variations,system and/or model instabilities, etc.); preferences; and/or the like.

Although the term “block” may be used herein to connote differentelements illustratively employed, the term should not be interpreted asimplying any requirement of, or particular order among or between,various blocks disclosed herein. Similarly, although illustrativemethods may be represented by one or more drawings (e.g., flow diagrams,communication flows, etc.), the drawings should not be interpreted asimplying any requirement of, or particular order among or between,various steps disclosed herein. However, certain embodiments may requirecertain steps and/or certain orders between certain steps, as may beexplicitly described herein and/or as may be understood from the natureof the steps themselves (e.g., the performance of some steps may dependon the outcome of a previous step). Additionally, a “set,” “subset,” or“group” of items (e.g., inputs, algorithms, data values, etc.) mayinclude one or more items, and, similarly, a subset or subgroup of itemsmay include one or more items. A “plurality” means more than one.

DETAILED DESCRIPTION

Various aspects of the present disclosure relate to apparatuses,methods, and systems directed toward neuroendocrine modulation of apatient's adrenal gland. Stimulation for depolarization of chromaffincell membrane or splanchnic nerve effect within the adrenal medulla, forpain and non-pain symptoms of chronic fatigue syndrome and fibromyalgiaand other disease states with neurotransmitter or neurohormonaldysfunction. Chromaffin cells in the adrenal medulla synthesize, store,and secret catecholamines (e.g., norepinephrine, epinephrine). Adrenalgland stimulation may lead to an increase, or produce a blocking effectin the activity of several of the catecholamine biosynthetic enzymes,and to an increase or decrease in the rate of catecholamine biosynthesisor chromaffin cell exocytosis or chromaffin cell sensitivity therebycausing secretion or blocking of catecholamines and of other chromaffingranule constituents from the chromaffin cells.

Various aspects of the present disclosure also relate to apparatuses,methods, and systems directed toward stimulation of the adrenal medullathat modulates the release of L-dopa into the systemic circulation. Thestimulation in this regard may be an alternative to, or delivered inparallel with, oral pharmacologic therapy and, in embodiments, may bedirected toward lessoning symptoms of degenerative neurological diseasessuch as Parkinson's disease. Parkinson's disease is a progressiveneurodegeneration of the central nervous system, e.g., the basalganglia, with a loss of dopamine production from dopanergic neuronswithin the substantia nigra of the brain or the formation of Lewy bodies(protein deposits inside of nerve cells). This results in the many motorabnormalities seen with Parkinson patients. Embodiments of the medicaldevices and methods discussed herein deliver stimulation to the adrenalmedulla or peripheral sympathetic nerve(s) to modulate the release ofL-dopa into the systemic circulation, as an alternative to, or inparallel with, oral pharmacologic therapy.

Electrical stimulation of the adrenal gland, specifically the medulla,has shown to modulate the release of dopamine in concert withnorepinephrine. L-dopa is the precursor to dopamine and dopamine is theprecursor for norepinephrine, all sharing the same source, tyrosine,within the medulla. L-dopa may cross the blood-brain-barrier and, thus,may facilitate keeping dopamine within a certain safety zone to mitigateblood pressure and/or gastrointestinal effects. In embodiments, thestimulation may be delivered, for example, based on individual clinicalsigns, with patients adjusting stimulation as needed, or based on asensor with automatic dosing and reprogramming of the stimulationparameters based on patient needs.

FIG. 1 is an example illustration of an adrenal gland therapy system100, which includes an adrenal gland therapy lead 102 and a controller104 in accordance with embodiments of the disclosure. The lead 102 mayinclude an elongated cylindrical lead body 106. The lead 102 includes anumber of electrodes 108 arranged on the lead body 106. The electrodes108 may be arranged circumferentially around the lead 102 as ringelectrodes mounted around the lead body 106. In embodiments, theelectrodes 108 may extend at least approximately around thecircumference of the lead body 106. In embodiments, one or more of theelectrodes 108 may extend partially around the circumference of the leadbody 106. In some instances, for example, the plurality of electrodes108 may be segmented electrodes that are circumferentially and axiallydisposed about the lead body 106. Each of the plurality of illustratedelectrodes 108 is labeled E1-E8, however the actual number and shape ofleads and electrodes vary according to the application.

As shown, the adrenal gland therapy lead 102 is operatively coupled tothe controller 104. A connector 110 arranged with the controller 104couples an end of the adrenal gland therapy lead 102 to the controller104, thereby operatively (e.g., communicatively, electrically, and/orphysically) coupling the electrodes 108 to the internal electronicswithin the controller 104. In embodiments, the controller 104 may beconfigured to communicate wirelessly with one or more leads 102, inwhich case, the controller 104 may include one or more wirelesscommunication antennas, coils, and/or the like. The controller 104 mayalso include a housing 112, which contains and houses electronic andother components. In embodiments, the controller 104 may include a pulsegenerator that may be implantable within a patient (e.g., an implantablepulse generator (IPG)), or may be configured to be positioned externalto the patient. In instances where the controller 104 is implantable,the housing 112 may be formed of an electrically conductive,biocompatible material, such as titanium, and may form a hermeticallysealed compartment wherein the internal electronics are protected fromthe body tissue and fluids.

The housing 112 may enclose sensing circuitry 114 configured to receive,from one or more of the electrodes 108, physiological signals obtainedby the one or more electrodes 108. The housing 112 may also enclosepulse generation circuitry 116 that delivers stimulation energy via oneor more of the electrodes 108. According to various embodiments, thesensing circuitry 114 (or aspects thereof) and/or the pulse generationcircuitry 116 (or aspects thereof) may be configured to be implanted inthe patient and/or disposed external to the patient. That is, forexample, in embodiments, the sensing circuitry 114 and the pulsegeneration circuitry 116 may be integrated within a processor disposedin an implantable medical device (e.g., the controller 104) and/or anexternal medical device. The sensing circuitry 114 (or aspects thereof)and/or the pulse generation circuitry 116 (or aspects thereof) may beimplemented in any combination of hardware, firmware, and software. Forexample, the sensing circuitry 114 may be, or include, a firstalgorithm, virtual processor, and/or process implemented by a processor,and, similarly, the pulse generation circuitry 116 circuit may be, orinclude, a second algorithm, virtual processor, and/or processimplemented by a processor. In embodiments, the sensing circuitry 114may be, or include, a first set of physical and/or virtual circuitelements, and, similarly, the pulse generation circuitry 116 may be, orinclude, a second set of physical and/or virtual circuit elements.

In embodiments, the controller 104 may include a programmablemicro-controller or microprocessor, and may include one or moreprogrammable logic devices (PLDs) or application specific integratedcircuits (ASICs). In some implementations, the controller 104 mayinclude memory as well. Although embodiments of the present system 100are described in conjunction with a controller 104 having amicroprocessor-based architecture, it will be understood that thecontroller 104 (or other device) may be implemented in any logic-basedintegrated circuit architecture, if desired. The controller 104 mayinclude digital-to-analog (D/A) converters, analog-to-digital (ND)converters, timers, counters, filters, switches, and/or the like.

The sensing circuitry 114 may be configured to receive a physiologicalsignal obtained by one or more of the electrodes 108, and analyze thereceived physiological signal to identify a therapy region. According toembodiments, the physiological signal may include intrinsic electricalactivity, a physiological response to an applied stimulation signal,and/or the like. For example, the sensing circuitry 114 may beconfigured to obtain a physiological signal that is a response to astimulation signal administered using one or more of the electrodes 108,and to analyze that signal to identify a therapy location. Inembodiments, the sensing circuitry 114 may be configured to evaluatemotion of the patient, electrical activity of the adrenal gland, and/orother physiological signals to identify a therapy region.

The therapy region may be, in embodiments, a region including a portionof an adrenal gland that is identified as being likely to be associatedwith an adrenal gland condition. For example, in implementations usedfor treating disorders such as chronic fatigue syndrome, fibromyalgia,orthostatic intolerance, irritable bowel syndrome (IBS), Crohn'sdisease, mood disorders/depression, or other disease states withneurotransmitter or neurohormonal dysfunction, a clinician may insertthe adrenal gland therapy lead 102 near or on a region of one or both ofthe patient's adrenal glands associated with the disorder, operate thecontroller 104 (e.g., manually, if the controller 104 is external, andvia telemetry if the controller 104 is implanted), causing thecontroller 104 to deliver stimulation energy to a selected region viaone or more of the electrodes 108. By evaluating an electrical responseobtained by one or more of the electrodes 108, the controller 104 and/orthe clinician may determine whether the selected region is a therapyregion (e.g., the selected region may be identified as a therapy regionif the physiological response to the stimulation indicates a therapeuticeffect). In embodiments, the clinician may identify a therapy region bydetermining a region of the adrenal gland(s) for which administeringstimulation energy results in at least some improvement in symptoms.

The stimulation energy may be in the form of a pulsed electricalwaveform to one or more of the electrodes 108 in accordance with a setof stimulation parameters, which may be programmed into the controller104, transmitted to the controller 104, and/or the like. Stimulationparameters may include, for example, electrode combinations that definethe electrodes that are activated as anodes (positive), cathodes(negative), turned on, turned off (zero), percentage of stimulationenergy assigned to each electrode (fractionalized electrodeconfigurations), and/or electrical pulse parameters, which define thepulse amplitude (measured in milliamps or volts depending on whether thecontroller 104 supplies constant current or constant voltage to one ormore of the electrodes 108), pulse duration (measured in microseconds),pulse rate (measured in pulses per second), pulse waveform, and/or burstrate (measured as the stimulation on duration X and stimulation offduration Y). The pulse generation circuitry 116 may be capable ofdelivering the stimulation energy to the one or more of the electrodes108 over multiple channels or over only a single channel. Stimulationenergy may be used to identify therapy regions and/or to providestimulation therapy to identified therapy regions or alter therapyregions over time to prevent exhaustion in one location.

Stimulation energy may be transmitted to the tissue in a monopolar (orunipolar) or multipolar (e.g., bipolar, tripolar, etc.) fashion.Monopolar stimulation occurs when a selected one or more of theelectrodes 108 is activated and transmits stimulation energy to tissue.Bipolar stimulation, a type of multipolar stimulation, occurs when twoof the electrodes 108 are activated as anode and cathode, so thatstimulation energy is transmitted between the activated electrodes.Multipolar stimulation also may occur when more than two (e.g., three,four, etc.) of the electrodes 108 are activated, e.g., two as anodes anda third as a cathode, or two as cathodes and a third as an anode. Incertain instances, the pulse generation circuitry 116 may individuallycontrol the magnitude of electrical current flowing through each of theelectrodes. In these instances, current generators may be used to supplycurrent-regulated amplitudes to selectively generate independent currentsources for one or more of the electrodes 108.

FIG. 2 is a plan view of an adrenal gland therapy system 200 inaccordance with embodiments of the disclosure. The adrenal gland therapysystem 200 may include at least one implantable adrenal glandstimulation lead 202, 204, a pulse generator (PG) 206, an externalremote controller (RC) 208, a clinician's programmer (CP) 210, and anexternal charger 214. In certain instances, the PG 206 may beoperatively coupled (and, in embodiments, physically coupled) to one orboth of the adrenal gland stimulation leads 202, 204, which may carry anumber of electrodes 216 arranged in an array. The PG 206 may includepulse generation circuitry that delivers electrical stimulation energyin the form of a pulsed electrical waveform (i.e., a temporal series ofelectrical pulses) to the plurality of electrodes 216 in accordance witha set of stimulation parameters. The PG 206 may be an implantable PG(and IPG), an external PG, or may represent an operatively coupledsystem including one or more implantable devices and/or one or moreexternal devices.

In certain instances, the RC 208 may be used to telemetrically controlthe PG 206 via a communications link 226. The RC 208 may also modifyprogrammed stimulation parameters to actively control thecharacteristics of the electrical stimulation energy output by the PG206. The RC 208 may perform these functions by indirectly communicatingwith the PG 206 through the RC 208, via a communications link 226.Alterations to the stimulation parameters or stimulation characteristicsmay be altered using the CP 210. The CP 210 may directly communicatewith the PG 206 and via a communications link. The external charger 214may be a portable device used to charge the PG 206 via a charging link230, which may be, e.g., an inductive charging link, a radio frequency(RF) charging link, illumination, ultrasound, magnetics, and/or thelike.

In embodiments, of the communication links 226, 228, and 230 may be, orinclude, a wireless communication link such as, for example, ashort-range radio link, such as Bluetooth, IEEE 802.11, a proprietarywireless protocol, and/or the like. In embodiments, for example, one ormore of the communication links 226, 228, and 230 may utilize BluetoothLow Energy radio (Bluetooth 4.1), or a similar protocol, and may utilizean operating frequency in the range of 2.40 to 2.48 GHz. The term“communication link” may refer to an ability to communicate some type ofinformation in at least one direction between at least two devices, andshould not be understood to be limited to a direct, persistent, orotherwise limited communication channel. That is, according toembodiments, a communication link may be a persistent communicationlink, an intermittent communication link, an ad-hoc communication link,and/or the like. A communication link may refer to direct communicationsbetween one or more devices, and/or indirect communications that travelbetween the one or more devices via at least one other device (e.g., arepeater, router, hub, and/or the like). A communication link mayfacilitate uni-directional and/or bi-directional communication betweenthe linked devices.

Any number of a variety of communication methods and protocols may beused, via communication links, to facilitate communication betweendevices in the adrenal gland therapy system 200. For example, wiredand/or wireless communications methods may be used. Wired communicationmethods may include, for example and without limitation, traditionalcopper-line communications such as DSL, broadband technologies such asISDN and cable modems, and fiber optics, while wireless communicationsmay include cellular communications, satellite communications, radiofrequency (RF) communications, infrared communications, induction,conduction, acoustic communications, and/or the like.

The illustrative components shown in FIGS. 1 and 2 are not intended tosuggest any limitation as to the scope of use or functionality ofembodiments of the disclosed subject matter. Neither should theillustrative components be interpreted as having any dependency orrequirement related to any single component or combination of componentsillustrated therein. Additionally, any one or more of the componentsdepicted in any of the FIGS. 1-2 may be, in embodiments, integrated withvarious other components depicted therein (and/or components notillustrated), all of which are considered to be within the ambit of thedisclosed subject matter. For example, the adrenal gland stimulationleads described with reference to FIG. 1, 3, or 4 may be used in theadrenal gland therapy system 200. Further, the adrenal gland therapysystem 200 may form a portion of the system described with reference toFIG. 6.

FIGS. 3A-C are example illustrations of an adrenal gland therapy lead300 having different configurations in accordance with embodiments ofthe disclosure. The adrenal gland therapy lead 300 may be used alone fordelivering therapy to an adrenal gland of a patient or as part ofapparatuses, methods, or systems for delivering therapy to an adrenalgland of a patient. The adrenal gland therapy lead 300 may include alead body 302 and a plurality of electrodes 304, 306, 308 arrangedtherewith. The adrenal gland therapy lead 300 may be connected with acontroller (e.g., as shown and descried with reference to FIGS. 1 and 2)to supply stimulation parameters to the plurality of electrodes 304,306, 308 arranged along the lead body 302. The lead body 302 may beconfigured to attach to a portion of the adrenal gland of the patientand engage a capsule of the adrenal gland. The lead body 302 may beconfigured to attach to a portion of the adrenal gland of the patientand engage the renal fascia, Gerota's fascia, the perirenal fat, theperiphrenic space, the anterior pararenal space, capsule or cortex. Inaddition and as described in further detail with reference to, forexample, FIGS. 5-6, at least one of the plurality of electrodes 304,306, 308 is configured to deliver stimulation energy to modulatecatecholamine release from chromaffin cells within the adrenal gland.The adrenal gland therapy lead 300 may also include a button 310configured to facilitate attachment of the lead to the adrenal gland,and stimulation thereof, and a helical anchor 312. In addition, one ormore of the plurality of electrodes 304, 306, 308 may be configured tosense the catecholamines released as a result of the deliveredstimulation energy. The button 310 may be formed of a material havingthe same properties as the lead body 302. In certain instances, thebutton 310 may be sized and shaped to provide a larger surface area ofstimulation, compared to the lead body 302, by arranging the pluralityof electrodes 304, 306, 308 thereon.

The button 310 may have a flexibility greater than the lead body 302,and may be configured to conform to the adrenal gland for attachmentthereto. More specifically, the button 310 may take the shape of theadrenal gland upon attachment thereto. In addition, the button 310 mayhave a width less than a width of the lead body 302. In certaininstances, the button 310 may be the portion of the adrenal glandtherapy lead 300 that attaches to a portion of the adrenal gland. Theadrenal glands are surrounded by a fatty capsule. The button 310 may beattached to an exterior surface of the capsule, within the capsule, aninterior surface of the capsule (e.g., between the capsule and theadrenal gland), or directly to the adrenal gland. Thus, the width of thebutton 310 may be approximately equal to or less than the capsule of theadrenal gland.

The helical anchor 312 may be configured to anchor to the lead body 302directly or indirectly (via the capsule) to the adrenal gland. Incertain instances, the helical anchor 312 may be configured as anelectrode in addition to the electrodes 304, 306, 308. A length of thehelical anchor 312 may be dependent on the anchoring location (e.g., alonger length when anchoring to the adrenal gland as compared toanchoring to the capsule or adrenal gland parenchyma). The helicalanchor 312 may be configured to mitigate against migration of the leadbody 302 when implanted, and ensure positive fixation on the adrenalgland.

In addition, the button 310 may be arranged along any portion of thelead body 302. As shown in FIG. 3A, the button 310 is arranged along anintermediate portion of the lead body 302. The lead body 302 includessome of the plurality of electrodes 304, 306, 308 on one side of thebutton 310, and others of the plurality of electrodes 304, 306, 308 onthe other side of the button 310. In certain instances, the position ofthe button 310 may be adjusted after implantation and/or fixation of thebutton 310 to the adrenal gland. The button 310 may frictionally engagethe lead body 302 such that a force applied by a physician wouldovercome the coupling of the button 310 to the lead body 302. The button310 may also be attached or couple to the lead body 302 by a medicaladhesive. A physician may adjust the positioning of the button 310 priorto implantation of the lead body 302, or after fixation of the button310 to the adrenal gland. As a result, the physician may adjust thepositioning of the plurality of electrodes 304, 306, 308 relative to theadrenal gland by shifting the button 310 along a length of the lead body302 prior to or after implantation and/or fixation of the button 310 tothe adrenal gland. As shown in FIG. 3B, the button 310 may be coupled orattached to a distal end of the lead body 302. In certain instances, thedistal end of the lead body 302 may include multiple buttons 310.

As shown in FIG. 3C, the plurality of electrodes 304, 306, 308 may bearranged around a perimeter of the button 310. In certain instances,arranging the plurality of electrodes 304, 306, 308 in this manner mayfacilitate directing stimulation energy to a smaller target area asopposed to across a length of the lead body 302.

FIG. 4A is an example illustration of an adrenal gland therapy lead 400and deployment system 402 in accordance with embodiments of thedisclosure. As shown in FIG. 4A, the adrenal gland therapy lead 400 isarranged within the deployment system 402. The adrenal gland therapylead 400 may be used alone for delivering therapy to an adrenal gland ofa patient or as part of apparatuses, methods, or systems for deliveringtherapy to an adrenal gland of a patient. The adrenal gland therapy lead400 may include a paddle component 404. The deployment system 402 mayhave a cylindrical shape with a circular opening at a distal endthereof. The adrenal gland therapy lead 400, including a lead body 406,may be loaded into the delivery system 402 at either end. In the loadingthe adrenal gland therapy lead 400 therein, the paddle component 404 maycollapse within the deployment system 402. As shown in FIG. 4A, thepaddle component 404 may roll upon itself to collapse within thedeployment system 402. In certain instances, the paddle component 404may fold, crease, pleat, or bend to collapse within the deploymentsystem 402. In certain instances, the deployment system 402 may be adelivery catheter.

FIG. 4B is an example illustration of the adrenal gland therapy lead 400shown in FIG. 4B, deployed from the deployment system 402 in accordancewith embodiments of the disclosure. FIG. 4B shows the adrenal glandtherapy lead 400 in a deployed/delivered configuration, whereas FIG. 4Ashows the adrenal gland therapy lead 400 in a delivery configuration.The paddle component 404 may be configured to expand to the deployedconfiguration, shown in FIG. 4B, in response to deployment from thedeployment system 402, and fold and collapse to the deliveryconfiguration, shown in FIG. 4A, in response to retraction within thedeployment system 402.

In addition and as shown in FIG. 4, the paddle component 404 may includea plurality of electrodes 408. The plurality of electrodes 408 arearranged on a paddle component 404, which may be arranged at a distalend of the lead body 406. The plurality of electrodes 408 may beconfigured to deliver stimulation energy therethrough to modulatecatecholamine release from chromaffin cells within at the adrenal glandsof the patient. The adrenal gland therapy lead 400 may be connected witha controller (e.g., as shown and descried with reference to FIGS. 1 and2) to supply stimulation parameters to the plurality of electrodes 408arranged with the paddle component 404. In addition, one or more of theplurality of electrodes 408 may be configured to sense a biomarkeraffected by the delivered stimulation energy. The sensed level ofcatecholamines released may be provided as feedback to the controller,which may alter the stimulation energy to achieve a desiredcatecholamine release level. In certain instances, the paddle component404 may include a thermoelectric element 410 arranged therewith. Thethermoelectric element 410 may provide a cooling effect to the adrenalgland. As described in further detail with reference to FIGS. 7A-B, thethermoelectric element 410 cooling the adrenal gland may also modulatecatecholamine release from chromaffin cells within the adrenal gland.More specifically, the thermoelectric element 410 (e.g., a Peltierelement) may be configured to cool the periglandular region of theadrenal gland. Applying the thermoelectric element 410 to the medulla(in, on or near) may a resultant effect of modulating the circulatinglevels of catecholamines within the bloodstream. In certain instances,the thermoelectric element 410 may apply a cooling effect within theintravascular space at, within or near the arterial supply to theadrenal gland. The thermoelectric element 410 may supply a cooling at atemperature range from 4 degrees Celsius to 32 degrees Celsius.

In certain instances, the lead body 406, or a portion thereof, may beconfigured to attach to a portion of an adrenal gland of the patient.More specifically, the paddle component 404 or the lead body 406 may beconfigured to engage a capsule of one of the adrenal glands. As notedabove, the paddle component 404 may be flexible and configured to engageand attach to the portion (e.g., the capsule) of the adrenal gland ofthe patient in the delivery configuration. The paddle component 404 mayat least partially conform to the adrenal gland, and mitigate againstresistant of the adrenal gland therapy lead 400. In certain instances,the paddle component 404 may be implanted between the capsule and theadrenal gland, which may further mitigate against resistant of theadrenal gland therapy lead 400. In other instances, the lead body 406and/or the paddle component 404 may also include a barb(s), a rigidhelix(s) and/or a talon(s) (not shown) for mechanical attachment to theadrenal gland. The lead body 406 may also include a suture feature(e.g., a suture hole, through which a suture may be arranged) to securethe lead body 406 in place. In other instances, in addition to or inplace of the mechanical attachment mechanisms, tissue glue, an adhesive,and/or a hydrogel or hydrogel/polymer type may be applied to the leadbody 406 and/or the paddle component 404 for adhesive attachment of thelead body 406 and/or the paddle component 404 to the adrenal gland.

FIG. 4C is an example illustration of the adrenal gland therapy lead 400shown in FIGS. 4A-B, deployed on an adrenal gland 412 in accordance withembodiments of the disclosure. As shown in FIG. 4C, the paddle component404 flexes and is configured to engage and attach to a portion of theadrenal gland 412. A physician placing the adrenal gland therapy lead400 may fluoroscopically visualize the orientation of the plurality ofelectrodes 408. In other instances, one or both of the lead body 406 andthe paddle component 404 may include radiopaque markers (not shown) toassist in visualizing the adrenal gland therapy lead 400. In certaininstances, the paddle component 404 may be a wrap or mesh.

FIG. 4D is an example illustration of the adrenal gland therapy lead 400shown in FIGS. 4A-C, including tethers 414, 416 in accordance withembodiments of the disclosure. The tethers 414, 416 may be attached tothe paddle component 404, and assist in repositioning of the paddlecomponent 404 relative to the adrenal gland 412. The tethers 414, 416may extend from the paddle component 404 and along the lead body 406.The tethers 414, 416 may extend along an entire length of the lead body406, in certain instances, such that a physician or user may manipulatethe tethers 414, 416. In other instances, the tethers 414, 416 may beattached to a portion of the lead body 406 such that manipulation of thelead body 406 indirectly manipulates the tethers 414, 416 and the paddlecomponent 404. Tensioning the tethers 414, 416 may withdraw the paddlecomponent 404 within the deployment system 402. As a result, tensioningthe tethers 414, 416 may allow for repositioning of the paddle component404 after deployment from the deployment system 402 or removal of theadrenal gland therapy lead 400 entirely. More specifically, the paddlecomponent 404 may be reconfigured to the delivery configuration, asshown in FIG. 4A, and redeployed if the positioning of the paddlecomponent 404 as desired or removed from the adrenal gland 412 alongwith the deployment system 402.

FIG. 5 is an example illustration of adrenal gland therapy leads 500,502 in accordance with embodiments of the disclosure. The adrenal glandtherapy leads 500, 502 are shown arranged on adrenal glands 504, 506 ofa patient. The adrenal glands 504, 506 are located above the patient'skidneys 508, 510, which are located on either side of the patient's venacava 512 and aorta 514. The adrenal gland therapy leads 500, 502 may bedelivered and attached, directly or indirectly to the adrenal glands504, 506 (or Gerota's fascia) by a laparoscopic procedure, openlaparotomy procedure, or other minimally invasive procedure.

Each of adrenal gland therapy leads 500, 502 may have a lead body 516,518 and a set of a plurality of electrodes 520, 522 arranged therewith.The plurality of electrode sets 520, 522 may be arranged longitudinallyalong the adrenal glands 504, 506. In certain instances, distal portionsof each lead body 516, 518 (e.g., portions having the plurality ofelectrode sets 520, 522) may have a greater flexibility (e.g., morepliable polyurethane) than other portions of the lead body 516, 518 orthe distal portions of each lead body 516, 518 may be formed from othermaterials (Pebax®, polyethylene, or Hytrel®) (polyester)). The addedflexibility of the lead body 516, 518 or portions of the lead body 516,518 may assist in mitigate against movement of the adrenal gland therapyleads 500, 502 when attached to the adrenal glands 504, 506. The addedflexibility of portions of the lead body 516, 518 may act as a strainrelief mechanism such that movement in other portions imparted on otherportions of the lead body 516, 518 is isolated and/or indirectlyabsorbed. In other instances, the lead body 516, 518 of each of theadrenal gland therapy leads 500, 502 may be attached to the adrenalglands 504, 506 with additional length or slack, between the adrenalglands 504, 506 and implant location of a controller coupled to eachlead body 516, 518, to provide additional flexibility for the absorptionof the patient's movement.

Each lead body 516, 518 may also include a button 524, 526. The button524, 526 of each lead body 516, 518 may have a flexibility greater thaneach lead body 516, 518, and may be configured to conform to the adrenalglands 504, 506 for attachment thereto. More specifically, each button524, 526 may take the shape of the adrenal glands 504, 506. The adrenalglands 504, 506 are surrounded by a fatty capsule (as shown in furtherdetail in FIG. 6). Each button 524, 526 may be attached to an exteriorsurface of the capsule, within the capsule, an interior surface of thecapsule (e.g., between the capsule and the adrenal gland), or directlyto the adrenal glands 504, 506.

In certain instance, each lead body 516, 518 and/or each button 524, 526may include a barb(s), a rigid helix(s), and/or a talon(s) formechanical attachment (not shown) to the adrenal glands 504, 506. Inother instances, in addition to or in place of the mechanical attachmentmechanisms, tissue glue, an adhesive, and/or a hydrogel may be appliedto each lead body 516, 518 and/or each button 524, 526 for attachment tothe adrenal glands 504, 506.

As noted above, the adrenal gland therapy leads 500, 502 may beconnected with a controller (e.g., as shown and descried with referenceto FIGS. 1 and 2). The controller may be configured to instruct deliveryof the stimulation energy through one or more of the electrodes in theplurality of electrode sets 520, 522 to modulate catecholamine releasefrom chromaffin cells within at least one of the adrenal glands 504,506. In certain instances, the controller may be configured tointermittently or continuously instruct delivery of the stimulationenergy through different combinations of the one or more of theelectrodes in the plurality of electrode sets 520, 522. Morespecifically, the controller (not shown) may include circuitry (e.g., asdescribed with reference to FIG. 1) that instructs delivery of thestimulation energy through one or more of the electrodes the pluralityof electrode sets 520, 522 on a duty cycle based on a metabolizationtime of catecholamine or clinical signs of the patient. The duty cyclemay include applying stimulation for 25% of a time period (e.g.,minutes, hour or day), and withhold stimulation for 75% the time period(e.g., minutes, hour or day). Continuous stimulation through one or moreof the adrenal glands 504, 506 may not be necessarily required forreaching therapeutic levels of catecholamine. The duty cycle control ofdelivery of the stimulation energy may reduce battery consumption andreduces chances of attenuated effectiveness over time due to adaptationor depletion of the adrenal glands 504, 506. In addition, thestimulation energy may be delivered at a frequency between 2 Hz and 20kHz (e.g., 2 Hz-50 Hz, 50 Hz-100 Hz, 100 Hz-500 Hz, 500 Hz-1 kHz, 1kHz-5 kHz, 5 kHz-10 kHz, 10 kHz-20 kHz or any combination thereof). Thestimulation energy may be applied as bursts of energy include pulses ata frequency between 2 Hz and 20 kHz or continuously. In addition, thefrequency and/or pulse width stimulation energy may also be alteredcontinuously or periodically altered over time. Altering the current,frequency and/or pulse width may reduce the chances of attenuatedeffectiveness of the stimulation over time due to adaptation of theadrenal glands 504, 506. In any of these instances, the stimulationenergy delivered may be altered in response to patient feedback based onthe physical symptoms of the patient.

In addition, stimulation energy may be transmitted to the adrenal glands504, 506 in a monopolar or multipolar (e.g., bipolar, tripolar, etc.)fashion. Monopolar stimulation occurs when a selected one or more of theelectrodes the plurality of electrode sets 520, 522 is activated andtransmits stimulation energy to tissue. Bipolar stimulation, a type ofmultipolar stimulation, occurs when two of the electrodes in theplurality of electrode sets 520, 522 are activated as anode and cathode,so that stimulation energy is transmitted between the activatedelectrodes. Multipolar stimulation also may occur when more than two(e.g., three, four, etc.) of the electrodes in the plurality ofelectrode sets 520, 522 are activated, e.g., two as anodes and a thirdas a cathode, or two as cathodes and a third as an anode. In addition,the stimulation energy may be fractionalized across one or more of theelectrodes in the plurality of electrode 520 and separatelyfractionalized across one or more of the electrodes in the plurality ofelectrode 522.

In certain instances, the controller may instruct delivery of thestimulation energy to one of the adrenal glands 504, 506 at a time. Inaddition, the controller may test between the electrode sets 520, 522 todetermine which of the electrode sets 520, 522 achieves a desiredresponse (e.g., based on patient feedback and or measuring the levels ofcatecholamine in the patient). More specifically and in certaininstances, one of the adrenal glands 504, 506 may respond to thestimulation differently than the other one of the adrenal glands 504,506. Thus, the controller may alter delivery of the stimulation totarget one or both of the adrenal glands 504, 506 to achieve a desiredresponse in response to measurement of a physiological sensor and/orinput from the patient. The simulation energy may be delivered to one orboth of the electrode sets 520, 522 to coordinate stimulation of theadrenal glands 504, 506. Both adrenal glands 504, 506 may be stimulatedat the same time, or the stimulation applied thereto could be staggered(e.g., according to a duty cycle as noted above). In certain instances,the coordinated stimulation of the adrenal glands 504, 506 may reducechances of attenuated effectiveness over time due toadaptation/tolerance of the adrenal glands 504, 506. The sensed level ofcatecholamines released may be provided as feedback to the controller,which may alter the stimulation energy to achieve a desiredcatecholamine release level.

The illustrative components shown in FIG. 5 are not intended to suggestany limitation as to the scope of use or functionality of embodiments ofthe disclosed subject matter. Neither should the illustrative componentsbe interpreted as having any dependency or requirement related to anysingle component or combination of components illustrated therein.Additionally, any one or more of the components depicted in any of theFIGS. 1-4 may be, in embodiments, integrated with various othercomponents depicted therein (and/or components not illustrated), all ofwhich are considered to be within the ambit of the disclosed subjectmatter. For example, the adrenal gland stimulation leads 500, 502 may beused in connection with the systems described with reference to FIG. 1and FIG. 2. In addition, the adrenal gland stimulation leads 500, 502may include the helical anchors 312 as shown in FIG. 3, or thethermoelectric element 410 or the paddle component 404 as shown in FIG.4.

FIG. 6 is an example illustration of an adrenal gland therapy system 600in accordance with embodiments of the disclosure. The adrenal glandtherapy system 600 includes a controller 602 (e.g., a pulse generator)that houses electronic and other components, an adrenal glandstimulation lead 604 coupled to the controller 602, and optionally aphysiological sensor 606. The adrenal gland stimulation lead 604 mayinclude a lead body 608 that is configured engage an adrenal gland 610of a patient 620. More specifically, the lead body 608 may configured toengage a capsule 612 of the adrenal gland 610. FIG. 6 also includes aninset portion highlighting the anatomy of the adrenal gland 610. Thecapsule 612 surrounds the adrenal gland 610, located above the kidney622. The lead body 608 may be attached to an exterior surface of thecapsule 612, within the capsule 612, an interior surface of the capsule612 (e.g., between the capsule and the remaining portions of the adrenalgland 610). The adrenal gland 610 also includes a cortex 614 whichproduces steroid hormones and a medulla 616. Chromaffin cells in themedulla 616 synthesize, store, and secret catecholamines (e.g.,norepinephrine, dopamine). The lead body 608 may also attach to thecortex 614 or medulla 616 (by way of a mechanical attachment mechanismas described, for example, with reference to FIGS. 3A-C or adhesiveattachment mechanism).

The lead body 608 also includes a plurality of electrodes 618 arrangedalong the lead body 608. The plurality of electrodes 618 may beconfigured to deliver stimulation energy through at least one of theplurality of electrodes 618 to modulate catecholamine release fromchromaffin cells within the adrenal gland 610. The controller 602,physically connected to the lead body 608 and electronically coupled tothe plurality of electrodes 618, may be configured to instruct deliveryof the stimulation energy through one or more of the plurality ofelectrodes 618 to modulate catecholamine release from chromaffin cells.Stimulation energy may be transmitted to the adrenal gland 610 in amonopolar or multipolar (e.g., bipolar, tripolar, etc.) fashion.Monopolar stimulation occurs when a selected one or more of theelectrodes the plurality of electrodes 618 is activated and transmitsstimulation energy to tissue. Bipolar stimulation, a type of multipolarstimulation, occurs when two of the electrodes in the plurality ofelectrodes 618 are activated as anode and cathode, so that stimulationenergy is transmitted between the activated electrodes. Multipolarstimulation also may occur when more than two (e.g., three, four, etc.)of the electrodes in the plurality of electrode sets 618 are activated,e.g., two as anodes and a third as a cathode, or two as cathodes and athird as an anode. In addition, the stimulation energy may befractionalized across one or more of the electrodes in the plurality ofelectrodes 618. The level of catecholamines released may be sensed bythe physiological sensor 606 and provided as feedback to the controller602, which may alter the stimulation energy to achieve a desiredcatecholamine release level.

In certain instances, the controller may be configured to intermittentlyor continuously instruct delivery of the stimulation energy throughdifferent combinations of the one or more of the plurality of electrodes618. In addition, the controller 602 may include circuitry (e.g., asdescribed with reference to FIG. 1) that instructs delivery of thestimulation energy through one or more of the plurality of electrodes618 on a duty cycle based on a metabolization time of catecholamine. Theduty cycle may include applying stimulation for 25% of a time period(e.g., minutes, hours, or days), and withhold stimulation for 75% thetime period (e.g., minutes, hours, or days). The duty cycle control ofdelivery of the stimulation energy may reduce battery consumption of thecontroller 602. In addition, the stimulation energy may be delivered ata frequency between 2 Hz and 20 kHz. The stimulation energy may beapplied as bursts of energy include pulses at a frequency between 2 Hzand 20 kHz, or continuously. In addition, the frequency and/or pulsewidth stimulation and/or current energy may also be altered continuouslyor periodically altered over time.

The stimulation energy delivered may be altered in response to patient620 feedback based on the physical symptoms of the patient 620.Additionally, the controller 602 may instruct alteration of thestimulation energy provided to one or more of the plurality ofelectrodes 618 based on patient feedback. Therapy may be customized bycalibrating to a target level of catecholamine release based on a changein physical symptoms or based on data obtained by the physiologicalsensor 606 and/or based on patient 620 or physician input on an externaldevice, communicatively coupled with the controller 602, that maycontrol the stimulation energy level. The patient 620 may be able toactivate/deactivate therapy correlating to his/her own perceptions oftheir symptoms (e.g., when they feel symptoms of chronic fatigue, theymay activate therapy). In these scenarios, the controller 602 mayinclude a self-limiting mechanism to avoid depletion of catecholamines(e.g., the controller 602 down-regulates or turns off stimulation toafter some period of time), so that a patient cannot cause depletion ofcatecholamines by requesting constant therapy.

The physiological sensor 606, in certain instances, may be configured tomeasure at least one physiological response of the patient 620. Inaddition to be being communicatively (and physically) coupled to thelead 604, the controller 602 may be communicatively coupled to thephysiological sensor 606. The controller 602 may be configured toreceive a signal from the physiological sensor 606 having dataindicative of the at least one physiological response of the patient620. Communication between the controller 602 and the physiologicalsensor 606 may be, or include, a wireless communication link such as,for example, a short-range radio link, such as Bluetooth, IEEE 802.11, aproprietary wireless protocol, and/or the like (as is described infurther detail with reference to FIG. 2). The controller 602 may alsoanalyze the signal from the physiological sensor 606 to calculatealteration of the stimulation energy, and communicate with the lead 604to alter the stimulation energy based on analysis of the signal.

In certain instances, the physiological sensor 606 may be a separatesensor configured to receive physiological signals. In other instances,the physiological sensor 606 may be the controller 602 itself. Further,the physiological sensor 606 may be a remote implantable or wearablemonitoring system (in communication with the controller 602). Thephysiological sensor 606 may also be a separate sensing lead thatconnects into the controller 602. The separate sensing lead may monitorssignals from another target away from an adrenal gland 610 of a patient620 to capture one or more physiological signals (e.g., indicative ofblood pressure). The adrenal gland therapy system 600 may include one ormore of these aspects as the physiological sensor 606.

In certain instances, the physiological sensor 606 may be configured tomeasure at least one of: heart rate of the patient 620, heart ratevariability of the patient 620 (such as modulation in S1/S2 amplitudeswith respiration), respiration rate of the patient 620, activity levelof the patient 620, catecholamine levels of the patient 620 (e.g.,chemosensor), metanephrine levels, metanephrine:creatinine (urine) ratiolevels, metanephrine as a surrogate for plasma norepinephrine, bodyposition, of the patient 620, body temperature of the patient 620,temperature of the adrenal gland 610, cardiac output of the patient 620,and arterial pressure of the patient 620, or any combination thereof(e.g., heart rate/respiration rate ratio). The activity level of thepatient 620 may assist in informing the controller 602 whetherstimulation energy should be altered (e.g., increased or blocked) due toan magnitude of change noted in the circulation and of circulatingcatecholamines. In certain instances, the physiological sensor 606 maybe implanted in the bladder and determine the urine metanephrine levelsof the patient 620, which is a surrogate for norepinephrine levels. Achange in the above noted physiological responses may require amodulation the exocytosis or metabolization of catecholamines, for aresultant change in the physiological responses necessary. As a result,the controller 602 may alter (increase or decrease) the stimulationenergy to alter modulate the release of catecholamines from the adrenalgland 610 to maintain a desired level of catecholamines in the patient620.

In certain instances, the physiological sensor 606 may be configured tomeasure the body temperature of the patient 620. The physiologicalsensor 606 may also be configured to measure the cardiac output, strokevolume of the heart (e.g., S1 indicative of contractility or S2 asindicative of blood pressure changes due to sympathetic activity)contractility body of the heart, and/or mean arterial pressure/pulsepressures/systolic/diastolic of the patient 620 (via intra-arterial orperi-arterial approaches). The physiological sensor 606 may also measureother surrogates of catecholamine levels, or pain or non-pain symptomsof various disease states with neurohormonal or neurotransmitterdysfunction such as fibromyalgia (e.g., as indicated by exhaustion),chronic fatigue, sleep apnea, or the like. In certain instances, thephysiological sensor 606 may be configured to measure surrogates ofcatecholamine levels associated with Postural Orthostatic TachycardiaSyndrome (POTS), orthostatic hypotension (OH), orthostatic intolerance(OI), or surrogates of catecholamine levels associated with heartfailure and migraines, all which have a cause and effect due to changesin circulating catecholamine levels. The physiological sensor 606 mayalso measure decreased positive expiratory pressure (PEP), decreased rawleft ventricular ejection time (LVET) and/or increased LVET correctedfor heart rate. A change in the above note physiological responses maycall for a modulation of the metabolization and exocytosis ofcatecholamines. As a result, the controller 602 may modulate thestimulation energy to modulate the release of catecholamines from theadrenal gland 610 to maintain a desired level of catecholamines in thepatient 620.

The coordinated stimulation provided by the controller 602 may provide aclosed-loop system which uses markers of systemic catecholamines ordisease state to optimize therapy. In certain instances, two or morephysiological parameters to provide the controller 602 with closed-loopcontrol and enable predictive power to provide therapy only when neededor otherwise enabling improved therapy titration (e.g. stimulationamplitude, charge) and optimize clinical outcomes. To address eithersteady state deficiency or a transient deficiency (ability to rampup/down quickly) of the adrenal gland 610 (or glands), the system 600may use more than one physiological sensor 606 that communicate with thecontroller 602 as described above. The sensors may provide additionalquantification, measurement, and tracking of the catecholamine levels ordisease status as a function of activity to optimize therapy. Themeasurements of the various physiological sensors may be collected bythe controller 602 and aggregated to alter delivery of the stimulationenergy provided through the plurality of electrodes 618.

The physiological sensor 606 may measure the steady state deficiency ofthe catecholamines levels of the patient 620 by determining thephysiological response measured by the physiological sensor 606 at agiven steady state activity level. A transient deficiency may bemonitored by looking at “transient” physiological sensor 606measurements around activity state transition. In certain instances, adesirable response will be quick and more like an “underdamped” systemwith respect to maintaining the catecholamines levels of the patient620, whereas a poor performance would look like an over-damped system.In certain instances, the controller 602 may be programmed based onpatient customization. For example, a patient may prefer stimulationenergy that is associated with lower systemic catecholamines. Thus, thecontroller 602 may program the stimulation to iterate in this manner.Another patient may prefer a state with higher systemic catecholamine,which would result in different stimulation energy (e.g., as compared toa patient that prefers lower systemic catecholamines). The controller602 may be programmed with references within patients such that thestimulation energy may change based on activity level and time of day(awake/sleeping). Biomarker data could be used to calibrate thepatients' preferences (increase or decrease) in systemic catecholaminelevels in a closed loop system on a patient-by-patient basis.

As a specific example, the physiological sensor 606 may be configured tomonitor heart rate activity. In the patient 620, the physiologicalsensor 606 may continuously record heart rate (HR) and activity(movement) information (e.g., using an accelerator), or body position(e.g., orthostatic imbalance) and parse the data stream into discreteactivity bands. The time axes are separated in terms of transitionsbetween the activity bands. HR data around the transitions may yieldmetrics for a transient deficiency, whereas HR data from in-betweentransitions and sufficiently away from the transitions may yield datafor a steady state deficiency. In certain instances, in place of oralong with monitoring the heart rate of the patient 620, thephysiological sensor 606 may measure heart sounds. The heart sounds mayprovide an indication as to whether the patient 620 is awake or asleepto influence modulation of catecholamine levels. More specifically, whenthe patient 620 is sleeping, the controller 602 may be programmed tooptimize (decrease) catecholamine levels to avoid insomnia by decreasingstimulation levels provided through the plurality of electrodes 618 ascompared to when the patient is awake. The stimulation parameters mayalso be maintained to ensure catecholamine levels stay above a lowerlimit (low circulating catecholamine levels may be associated with apatient's current challenges with inability to sleep) or below an upperlimit. in addition, when the patient 620 is exercising, the controller602 may ensure optimal levels to reduce pain and fatigue (e.g., modulatelevels based on baselines changes to exertion or stress) and ensurecatecholamine levels stay above a lower limit (higher circulating levelsmay be associated with these patients' current challenges with lowertolerance for prolonged activity). As a result, the controller 602 maybe configured to ensure appropriate modulation of catecholamine levels,which may vary when the patient is exercising, at rest or undergoingstressful experiences.

In certain instances, the plurality of electrodes 618 are stimulationelements configured to deliver stimulation energy therethrough. Thestimulation elements 618 may be configured to deliver one or more ofelectrical stimulation, light stimulation, sound stimulation, thermalstimulation, and magnetic stimulation. In addition, the stimulationelements 618 may be configured to modulate release of L-dopa into abloodstream of the patient. The stimulation elements 618 may beconfigured to stimulate the adrenal gland 610 (or glands) and facilitaterelease of L-dopa into the blood stream to maintain dopamine levels ofthe patient within a zone. Abnormal levels of L-dopa have beenassociated with degenerative diseases such as Parkinson's disease.

The controller 602, physically connected to the lead body 608 andelectronically coupled to the plurality of stimulation elements 618, maybe configured to instruct delivery of the stimulation energy through oneor more of the plurality of stimulation elements 618 to modulate L-doparelease into the blood stream. Stimulation energy may be transmitted tothe adrenal gland 610 in a monopolar or multipolar (e.g., bipolar,tripolar, etc.) fashion. Monopolar stimulation occurs when a selectedone or more of the stimulation elements of the plurality of stimulationelements 618 is activated and transmits stimulation energy to tissue.Bipolar stimulation, a type of multipolar stimulation, occurs when twoof the electrodes of the plurality of stimulation elements 618 areactivated as anode and cathode, so that stimulation energy istransmitted between the activated stimulation elements. Multipolarstimulation also may occur when more than two (e.g., three, four, etc.)of the stimulation elements of the plurality of stimulation elements 618are activated, e.g., two as anodes and a third as a cathode, two ascathodes and a third as an anode, and/or the like. In addition, thestimulation energy may be fractionalized across one or more of theelectrodes of the plurality of stimulation elements 618. In certaininstances, the level of L-dopa released, the amount of L-dopa in theblood stream, and/or the amount of dopamine in the patient associatedwith the released L-dopa may be sensed by the physiological sensor 606and provided as feedback to the controller 602, which may alter thestimulation energy to achieve and/or maintain a desired L-dopa releaselevel and/or a level of dopamine in the blood stream.

In certain instances, the controller may be configured to intermittentlyor continuously instruct delivery of the stimulation energy throughdifferent combinations of the one or more of the plurality ofstimulation elements 618. In addition, the controller 602 may includecircuitry (e.g., as described with reference to FIG. 1) that instructsdelivery of the stimulation energy through one or more of the pluralityof stimulation elements 618 on a duty cycle based on a metabolizationtime of L-dopa. Embodiments of the duty cycle may include, for example,applying stimulation for 25% of a time period (e.g., minutes, hours, ordays), and withholding stimulation for 75% of the time period (e.g.,minutes, hours, or days). The duty cycle control of delivery of thestimulation energy may reduce battery consumption of the controller 602.In addition, the stimulation energy may be delivered at a frequencybetween approximately 2 Hz and approximately 20 kHz. The stimulationenergy may be applied as bursts of energy that include pulses at afrequency between approximately 2 Hz and approximately 20 kHz, orcontinuously. In addition, the frequency and/or pulse width stimulationand/or current energy may also be altered continuously or periodicallyover time.

The stimulation energy delivered may be altered in response to patient620 feedback based on the physical symptoms of the patient 620.Additionally, the controller 602 may instruct alteration of thestimulation energy provided to one or more of the plurality ofelectrodes 618 based on patient feedback. Therapy may be customized bycalibrating to a target level of L-dopa release based on a change inphysical symptoms (e.g., tremors, muscle rigidity, and/or bradykinesia),based on data obtained by the physiological sensor 606, and/or based onpatient 620 and/or physician input via an external device,communicatively coupled with the controller 602, that may control thestimulation energy level. The patient 620 may be able toactivate/deactivate therapy correlating to his/her own perceptions oftheir symptoms (e.g., when they feel of tremors, they may activatetherapy).

The physiological sensor 606, in certain instances, may be configured tomeasure at least one physiological response of the patient 620. Inaddition to being communicatively (and physically) coupled to the lead604, the controller 602 may be communicatively coupled to thephysiological sensor 606. The controller 602 may be configured toreceive a signal from the physiological sensor 606 having dataindicative of at least one physiological response of the patient 620.Communication between the controller 602 and the physiological sensor606 may be, or include, a wireless communication link such as, forexample, a short-range radio link, such as Bluetooth, IEEE 802.11, aproprietary wireless protocol, and/or the like (as is described infurther detail with reference to FIG. 2). The controller 602 may alsoanalyze the signal from the physiological sensor 606 to calculatealteration of the stimulation energy, and communicate with the lead 604to alter the stimulation energy based on analysis of the signal.

In certain instances, the physiological sensor 606 may be a separatesensor configured to receive physiological signals. In other instances,the physiological sensor 606 may be the controller 602 itself. Further,the physiological sensor 606 may be a remote implantable or wearablemonitoring system (in communication with the controller 602). Thephysiological sensor 606 may also be a separate sensing lead thatconnects into the controller 602. The separate sensing lead may monitorsignals from another target away from an adrenal gland 610 of a patient620 to capture one or more physiological signals (e.g., indicative ofblood pressure). The adrenal gland therapy system 600 may include one ormore of these aspects as the physiological sensor 606.

In certain instances, the physiological sensor 606 may be at least oneof a vascular sensor configured to measure hypotension, a sensorconfigured to measure blood pressure of the patient, a bioimpedencesensor configured to measure blood pressure of the patient, an electoralsensor configured to assess vascular tone and/or heart pulse transittime, an optical sensor configured to assess vascular tone and/or heartpulse transit time, and an accelerometer configured to measure physicalmovement of the patient.

In certain instances, the plurality of simulation elements 618 may beconfigured to deliver stimulation energy to peripheral sympatheticnerves to modulate the release of L-dopa into the bloodstream. The lead604 may be arranged to stimulate the peripheral sympathetic nervesrather than the adrenal gland 610, or, in embodiments, an addition lead604 may be arranged to stimulate the peripheral sympathetic nerves alongwith a lead 604 stimulating the adrenal gland 610. In addition, a lead614 may also be placed in the brain to provide stimulation energy fordeep brain stimulation energy. This stimulation may also affect releaseof L-dopa.

The illustrative components shown in FIG. 6 are not intended to suggestany limitation as to the scope of use or functionality of embodiments ofthe disclosed subject matter. Neither should the illustrative componentsbe interpreted as having any dependency or requirement related to anysingle component or combination of components illustrated therein.Additionally, any one or more of the components depicted in any of theFIGS. 1-5 may be, in embodiments, integrated with various othercomponents depicted therein (and/or components not illustrated), all ofwhich are considered to be within the ambit of the disclosed subjectmatter. For example, the adrenal gland stimulation lead 602 may be usedin connection with the systems described with reference to FIG. 1 andFIG. 2. In addition, the adrenal gland stimulation lead 604 may includethe helical anchors 312 as shown in FIG. 3, or the thermoelectricelement 410 or the paddle component 404 as shown in FIG. 4.

FIG. 7A is an example illustration of another adrenal gland therapysystem in accordance with embodiments of the disclosure. FIG. 7 showsvarious aspects of the anatomy 700 in a patient including the aorta 704,the vena cava 702, the right kidney 706, the left kidney 708, the rightadrenal gland 710, and the left adrenal gland 712. Certain aspects ofthe vasculature are also highlighted including the right superiorsuprarenal arteries 714, right middle suprarenal artery 716, rightinferior suprarenal artery 718, left superior suprarenal arteries 720,left middle suprarenal artery 722, left inferior suprarenal artery 724,and the right and left interior phrenic arteries 726. The adrenal glandtherapy system may include attaching or coupling a thermoelectricelement (shown in FIG. 7B) to one or more locations 728 a-h of thevasculature. The thermoelectric element may cool one or both of theadrenal glands 710, 712 to modulate catecholamine release fromchromaffin cells therein.

FIG. 7B is an example illustration of a cooling system 730 included withthe adrenal gland therapy system shown in FIG. 7A in accordance withembodiments of the disclosure. The cooling system 730 may be attached toone or more locations 728 a-h shown in FIG. 7A. At the locations 728a-h, the cooling system 730 cools blood flow into the adrenal glands710, 712. Cooling the blood may cool the periglandular region of theadrenal glands 710, 712, which may trigger catecholamine release fromchromaffin cells within the adrenal glands 710, 712. As a result, thecooling system 730 may have a resultant effect of increasing thecirculating levels of norepinephrine and dopamine within thebloodstream, similar to stimulation of the adrenal glands 710, 712. Thecooling system 730 may be used alone or in combination with thestimulation systems or leads discussed herein (e.g., FIGS. 1-6). Morespecifically, the cooling system 730 may include a controller 732. Thecontroller 732 may apply current to apply the cooling effect. Thecontroller 732 may also be coupled to adrenal gland stimulation leads,as discussed herein (e.g., FIGS. 1-6), to control stimulation applied tothe adrenal glands 710, 712. The controller 732 may apply cooling andstimulation concurrently, or alternate cooling and stimulation. This mayincrease the battery life of the controller 732 by reducing batteryconsumption and may also reduce chances of attenuated effectiveness overtime due to adaptation or depletion of the adrenal glands 710, 712.

The cooling system 730 may include at least one thermoelectric element(e.g., a Peltier element) to effect cooling of the adrenal gland 710,712. As shown in FIG. 7B, a stent or wrap 744 is arranged at one of thelocations 728 a-h of the vasculature in or around an artery 742. Incertain instances, the stent or wrap 744 may be arranged directly on oneor both of the adrenal glands 710, 712. The stent or wrap 744 includes athermoelectric element that is coupled to the controller 732 viainsulated wires 738, 740. The controller 732 may apply current 734, 736via the insulated wires 738, 740, and dissipate heat that results fromthe thermoelectric element. The cooling system 730 may supply a coolingat a temperature range from 4 degrees Celsius to 32 degrees Celsius.

The illustrative components shown in FIGS. 7A-B are not intended tosuggest any limitation as to the scope of use or functionality ofembodiments of the disclosed subject matter. Neither should theillustrative components be interpreted as having any dependency orrequirement related to any single component or combination of componentsillustrated therein. Additionally, any one or more of the componentsdepicted in any of the FIGS. 7A-B may be, in embodiments, integratedwith various other components depicted therein (and/or components notillustrated), all of which are considered to be within the ambit of thedisclosed subject matter. For example, the cooling system 730 may beused in connection with the systems described with reference to FIG. 1and FIG. 2 or the adrenal gland stimulation leads and systems describedwith reference to FIGS. 3-6.

FIG. 8 is a schematic block diagram of a leadless implantable medicaldevice (IMD) 800, in accordance with aspects of embodiments of thedisclosure. As shown in FIG. 8, the leadless implantable medical device800 includes a power source 802 that powers operational circuitry 804 ofthe leadless implantable medical device 800. The operational circuitry804 includes a controller 806 coupled to a memory 808. An oscillator 810coupled to the controller 806 may be used as a clocking mechanism toprovide timing functions to the controller 806. In certain instances,other types of clocking mechanisms may be used instead of, as well as,or in addition, to the oscillator 810. The operational circuitry 804also includes a communications component 812, a therapy circuit 814, anda physiological sensor 816. As shown in FIG. 3, the therapy circuit 814is coupled to stimulation elements 818 and 820 and is configured toprovide stimulation energy to the stimulation elements 818 and 820,which, in turn, provide the energy to a patient's adrenal gland. The IMD800 may include more than two stimulation elements 818 and 820. Thestimulation elements 818 and 820 may be configured to modulate releaseof L-dopa. Additionally, the communications component 812 may include atransceiver and/or an antenna.

The IMD 800 may also include a sensor 816 configured to sense andfacilitate analysis of L-dopa levels within the patient, L-dopa release,and/or dopamine levels within the patient that are associated withL-dopa. The sensor 816 may be, for example, a vascular sensor configuredto measure hypotension, a sensor configured to measure blood pressure ofthe patient, a bioimpedence sensor configured to measure blood pressureof the patient, an electoral sensor configured to assess vascular toneor heart pulse transit time, an optical sensor configured to assessvascular tone or heart pulse transit time, an accelerometer configuredto measure physical movement of the patient, and/or the like.

FIG. 9 is a schematic illustration of a portion of a patient's anatomy900 and an associated implantable system including an implantablemedical device (IMD) 902 attached to a portion of a patient's adrenalgland 904, in accordance with embodiments of the present disclosure. Theanatomy 900 shown in FIG. 9 includes adrenal glands 904, 906 (withGerota's fascia), which are located above the patient's kidneys 908,910, which are located on either side of the patient's vena cava 912 andaorta 914. The IMD 902 may include a leadless body 916 configured toengage the adrenal gland 904 (and/or periadrenal connective tissue), andat least one stimulation element 918 arranged with the leadless body916. The leadless body 916 may also be attached adjacent to one or bothof the adrenal glands 904, 906 (e.g., within the retroperitoneal spacesuch as the peritoneum or submuscular region (i.e. Longissimus muscles)above the adrenal glands 904, 906). The stimulation element 918 may beconfigured to deliver stimulation energy to modulate release of L-dopainto a bloodstream of the patient. In certain instances, the stimulationelement 918 may be configured to stimulate the adrenal gland 904 (orglands) and release of L-dopa into the blood stream to maintain dopaminelevels of the patient within a zone.

In certain instances, the stimulation element 918 is configured todeliver electrical stimulation, light stimulation, sound stimulation,thermal stimulation, and/or magnetic stimulation to the adrenal gland904 to modulate L-dopa release. The stimulation element 918 may bespecifically configured to deliver the intended type of stimulationenergy. The stimulation element 918 may be configured to facilitaterelease of L-dopa into the systemic circulation, which may lessenphysical symptoms of the patient in neurodegenerative diseases. L-doparelease may lessen at least one of tremors, muscle rigidity, andbradykinesia of the patient. The stimulation and modulation may be usedto keep dopamine (as a certain portion of L-dopa may be converted priorto crossing the blood-brain-barrier) levels within a certain safety zoneto mitigate blood pressure and/or other physical effects and, inembodiments, may be based upon individual clinical signs. The IMD 902may communicate with a controller 920 to effect stimulation through thestimulation element 918.

As shown in FIG. 9, the IMD 902 is a wireless electrode stimulatorassembly with the controller 920 configured to communicate with the IMD902. In certain instances, the controller 920 may be co-implanted andmay provide therapy and/or diagnostic data about the patient and/or thecontroller 920. In other instances, the controller 920 may be arrangedexternal to the patient. The IMD 902 may include circuitry to sense andanalyze the adrenal gland 904 electrical activity, and to determine ifand when a pacing electrical pulse needs to be delivered and, ininstances having multiple IMDs 902 (e.g., an IMD attached to adrenalgland 904), to determine which of the IMDs 902 should deliver the pulse.The controller 920 may have one or more sensors (e.g., as describedabove with reference to FIG. 8). The sensor or sensors may also bearranged with the leadless body 916. The aldosterone levels of thepatient may be sensed by the sensor and provided as feedback to thecontroller 920, which may alter the stimulation energy to achievedesired aldosterone levels of the patient.

The controller 902 may be configured to analyze the signal from thesensor to calculate alteration of the stimulation energy, and alter thestimulation energy based on analysis of the signal. The data indicativeof the L-dopa release levels of the patient may be measured by thesensor of the controller 920 and/or leadless body 916, which may be avascular sensor configured to measure hypotension, a sensor configuredto measure blood pressure of the patient, a bioimpedence sensorconfigured to measure blood pressure of the patient, an electoral sensorconfigured to assess vascular tone or heart pulse transit time, anoptical sensor configured to assess vascular tone or heart pulse transittime, an accelerometer configured to measure physical movement of thepatient, and/or the like.

In certain instances, the IMD 902 has an internal receiver that mayreceive communications and/or energy from the controller 920, which mayinclude a transmitter. The controller 920 may include a pulse generatorthat supplies an appropriate time-varying energy (e.g., current orvoltage) to the IMD 902. The IMD 902 may include a power source forstoring electrical energy, and may also have a triggering mechanism todeliver stored energy to the adrenal gland via the stimulation element918. The IMD 902 may be a passive stimulator such that stimulationenergy is transmitted via the controller 920, stored with the IMD 902,and stimulated in response to a prompt from the controller 920. In otherinstances, the IMD 902 may be an active stimulator and providestimulation based on control circuitry contained therein (e.g., asdescribed in further detail in FIG. 8).

Any number of a variety of communication methods and protocols may beused, via communication links, to facilitate communication betweendevices in the adrenal gland therapy system discussed herein. Forexample, wired and/or wireless communications methods may be used. Wiredcommunication methods may include, for example and without limitation,traditional copper-line communications such as DSL, broadbandtechnologies such as ISDN and cable modems, and fiber optics, whilewireless communications may include cellular communications, satellitecommunications, radio frequency (RF) communications, infraredcommunications, induction, conduction, acoustic communications, and/orthe like.

Modulation of aldosterone, consistent with the various aspects of thepresent disclosure, may be non-hemodynamic. Modulation can encompass aslow rise or abrupt rise. Blunting may have abrupt compensatory riseafter stimulation turned off, or may have residual blunting effectsprior to plasma rise after stimulation turned off. The discovery ofusing electrical stimulation to modulate aldosterone levels (as opposedto use of pharmaceutical drugs) was unexpected as stimulation was notthought to interact, affect, nor disrupt the RAAS as noted above.

Various modifications and additions can be made to the exemplaryembodiments discussed without departing from the scope of the presentdisclosure. For example, while the embodiments described above refer toparticular features, the scope of this disclosure also includesembodiments having different combinations of features and embodimentsthat do not include all of the described features. Accordingly, thescope of the present disclosure is intended to embrace all suchalternatives, modifications, and variations as fall within the scope ofthe claims, together with all equivalents thereof.

We claim:
 1. An apparatus for delivering therapy to an adrenal gland ofa patient, the apparatus comprising: a housing configured to attach to aportion of the adrenal gland of the patient; and a plurality ofstimulation elements arranged with the housing, the plurality ofelectrodes being configured to deliver stimulation energy through atleast one of the plurality of electrodes to modulate release of L-dopainto a bloodstream of the patient.
 2. The apparatus of claim 1, whereinthe plurality of stimulation elements are configured to stimulate theadrenal gland and release of L-dopa into the blood stream to maintaindopamine levels of the patient within a zone.
 3. The apparatus of claim1, wherein the housing is a leadless body housing configured to engagethe portion of the adrenal gland.
 4. The apparatus of claim 1, whereinthe housing is a lead body configured to engage the portion of theadrenal gland.
 5. The apparatus of claim 1, wherein the plurality ofstimulation elements are configured to deliver at least one ofelectrical stimulation, light stimulation, sound stimulation, thermalstimulation, and magnetic stimulation to the adrenal gland to modulatethe release of L-dopa.
 6. The apparatus of claim 1, further comprising asensor configured to measure the L-dopa levels within the patient andalter the stimulation energy delivered through the at least one of theplurality of stimulation elements to maintain the L-dopa release withina zone.
 7. The apparatus of claim 6, wherein the sensor is at least oneof a vascular sensor configured to measure hypotension, a sensorconfigured to measure blood pressure of the patient, a bioimpedencesensor configured to measure blood pressure of the patient, an electoralsensor configured to assess vascular tone or heart pulse transit time,an optical sensor configured to assess vascular tone or heart pulsetransit time, and an accelerometer configured to measure physicalmovement of the patient.
 8. The apparatus of claim 7, wherein thehousing comprises a communications component configured to communicatewireless signals, and the sensor is configured to measure the dopaminelevels associated with L-dopa within the patient and communicatefeedback to the communications component via wireless signals to alterthe stimulation energy delivered through the at least one of theplurality of stimulation elements to maintain the L-dopa release withina zone.
 9. The apparatus of claim 1, wherein the plurality ofstimulation elements are configured to delivery stimulation energy on aduty cycle based on a metabolization time of L-dopa within the patient.10. The apparatus of claim 1, wherein the delivery of stimulation energymodulates release of L-dopa to lessen at least one of tremors, musclerigidity, and bradykinesia of the patient.
 11. The apparatus of claim 1,wherein the plurality of stimulation elements are configured tointermittently or continuously instruct delivery of the stimulationenergy through the plurality of electrodes.
 12. A system for deliveringtherapy to an adrenal gland of a patient, the system comprising: ahousing configured to attach to a portion of the adrenal gland of thepatient; a plurality of stimulation elements arranged with the housing,the plurality of electrodes being configured to deliver stimulationenergy through at least one of the plurality of electrodes to modulaterelease of L-dopa into a bloodstream of the patient; and a sensorconfigured to measure dopamine levels within the patient associated withthe L-dopa release and alter the stimulation energy delivered throughthe at least one of the plurality of stimulation elements in responsethereto.
 13. The system of claim 12, wherein the sensor is at least oneof a vascular sensor configured to measure hypotension, a sensorconfigured to measure blood pressure of the patient, a bioimpedencesensor configured to measure blood pressure of the patient, an electoralsensor configured to assess vascular tone or heart pulse transit time,an optical sensor configured to assess vascular tone or heart pulsetransit time, and an accelerometer configured to measure physicalmovement of the patient.
 14. The system of claim 12, wherein the sensoris configured to measure a physical symptom of the patient associatedwith Parkinson's disease.
 15. The system of claim 12, wherein thecontroller is further configured to instruct delivery of the stimulationenergy through the at least one of the plurality of electrodes at afrequency between 2 Hz and 20 kHz.
 16. The system of claim 12, whereinthe plurality of stimulation elements are configured to stimulate theadrenal gland and release of L-dopa into the blood stream to maintaindopamine levels of the patient within a zone
 17. A method of deliveringtherapy to an adrenal gland of a patient, the method comprising:delivering a housing to a portion of the adrenal gland of the patient,the housing including a plurality of stimulation elements arranged withthe housing; and delivering stimulation energy through at least one of aplurality of electrodes leadless implantable medical to modulatealdosterone levels within the patient.
 18. The method of claim 17,further comprising delivering stimulation energy to peripheralsympathetic nerves to modulate the release of L-dopa into thebloodstream.
 19. The method of claim 17, further comprising deliveringdeep brain stimulation energy to the patient delivering stimulationenergy.
 20. The method of claim 17, further comprising measuring aphysical symptom of the patient associated with Parkinson's disease andaltering delivery of the stimulation in response thereto.